Inhibition of 11β-hydroxysteroid dehydrogenase Type 1(11β-HSD-1), an enzyme that catalyzes regeneration of active 11-hydroxy glucocorticoids from inactive 11-keto metabolites within target tissues, represents a novel approach to the treatment of the conditions associated with the Metabolic Syndrome, including hypertension, obesity, dyslipidemia, and Type 2 diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM). Inhibitors of this enzyme may also have utility to treat or prevent age-associated cognitive impairment. The therapeutic potential of inhibitors of 11β-HSD-1 has been reviewed: B. R. Walker and J. R. Seckl, “11β-Hydroxysteroid dehydrogenase Type 1 as a novel therapeutic target in metabolic and neurodegenerative disease,” Expert Opin. Ther. Targets, 7: 771-783 (2003).
WO 03/104207 (published 18 Dec. 2003), assigned to Merck & Co., describes a class of substituted 1,2,4-triazoles, which are potent inhibitors of the 11β-HSD-1 enzyme and therefore useful for the treatment of Type 2 diabetes, hyperglycemia, obesity, dyslipidemia, hypertension, and cognitive impairment. Specifically disclosed in WO 03/104207 is 3-[1-(4-chlorophenyl)-trans-3-fluorocyclobutyl]-4,5-dicyclopropyl-r-4H-1,2,4-triazole.
However, there is no disclosure in WO 03/104207 of the newly discovered crystalline monohydrate and anhydrate forms of 3-[1-(4-chlorophenyl)-trans-3-fluorocyclobutyl]-4,5-dicyclopropyl-r-4H-1,2,4-triazole of structural formula I below (hereinafter referred to as Compound I).
The present invention also discloses a novel crystalline toluene solvate of Compound I.